Local anesthetic activity of mixtures of cis- and trans-(2-dimethylaminomethylcycloheptyl)-2-alkoxyphenylcarbamates.

In a previous study, we synthesized two homologous series of racemic stereoisomeric cis- and trans-(2-dimethylaminomethylcycloheptyl)-2-alkoxyphenylcarbamates with alkyl chain lengths ranging from C1 to C8 and analyzed their local anesthetic activity. Here, we show that the local anesthetic activities of mixtures of cis-1 and trans-1 stereoisomers are higher than the sum of activities calculated for the individual stereoisomers at all molar fractions. We conclude that an appropriate ratio of cis- and trans-stereoisomers is necessary to achieve the maximum anesthetic activity of the studied stereoisomeric carbamates.

Three new aromatic sulfonamide inhibitors of carbonic anhydrases I, II, IV and XII.

4-Sulfamoyl-N-(3-morpholinopropyl)benzamide (I-1), N-(3-morpholinopropyl)benzene-1,4-disulfonamide (I-2) and N-(4-diethylaminoethoxybenzyl)benzene-1,4-bis(sulfonamide (I-3), were prepared and assayed as inhibitors of four carbonic anhydrase (CA) isoenzymes hCA I, hCA II, hCA IV and hCA XII. These compounds exhibited nanomolar half maximal inhibitory concentration (IC(50)) ranging from 58 to 740 nmol/L. All three aromatic sulfonamides show different activities for the isoenzymes studied with lowest affinity against isoenzyme hCA XII.

Gentiana asclepiadea and Armoracia rusticana can modulate the adaptive response induced by zeocin in human lymphocytes.

Zeocin is a member of bleomycin/phleomycin family of antibiotics isolated from Streptomyces verticullus. This unique radiomimetic antibiotic is known to bind to DNA and induce oxidative stress in different organisms producing predominantly single- and double- strand breaks, as well as a DNA base loss resulting in apurinic/apyrimidinic (AP) sites. The aim of this study was to induce an adaptive response (AR) by zeocin in freshly isolated human lymphocytes from blood and to observe whether plant extracts could modulate this response. The AR was evaluated by the comet assay. The optimal conditions for the AR induction and modulation were determined as: 2 h-intertreatment time (in PBS, at 4°C) given after a priming dose (50 µg/ml) of zeocin treatment. Genotoxic impact of zeocin to lymphocytes was modulated by plant extracts isolated from Gentiana asclepiadea (methanolic and aqueous haulm extracts, 0.25 mg/ml) and Armoracia rusticana (methanolic root extract, 0.025 mg/ml). These extracts enhanced the AR and also decreased DNA damage caused by zeocin (after 0, 1 and 4 h-recovery time after the test dose of zeocin application) to more than 50%. These results support important position of plants containing many biologically active compounds in the field of pharmacology and medicine.

Biological activity of plant extract isolated from Papaver rhoeas on human lymfoblastoid cell line.

Varied medicinal plants are known as a source of natural phytochemicals with antioxidant activities that can protect organisms from oxidative stress and from various chronic diseases. Papaver rhoeas has a long history of medicinal usage, especially for ailments in adults and children. The possible cytotoxicity, genotoxicity and potential antioxidant effect of plant extract isolated from flowers of Papaver rhoeas was investigated in human lymfoblastoid cell line (TK6). Antioxidant activity of this extract was determined using the DPPH assay. The plant extract exhibited dose dependent free radical scavenging ability. The growth activity assay was used for determination of cytotoxicity. To assess potential genotoxicity the comet assay was used. The lower extract concentrations (0.25 and 0.5 mg/ml) neither exerted cytotoxic, nor genotoxic effects in TK6 cells but they stimulated cell proliferation. The concentration 25 mg/ml scavenged almost 85% of DPPH free radical. On the other hand, this concentration had strong cytotoxic and genotoxic effect on TK6 cells. The balance between beneficial and harmful effects should be always considered when choosing the effective dose.

Synthesis and local anesthetic activity--lipophilicity relationships for a homological series of phenylcarbamic acid esters. Note II.

A homological series of new esters of 2-alkoxyphenylcarbamic acid and one ester of 2,6-dimethylphenylcarbamic acid were synthesized and assayed for surface local anesthetic activity. All compounds were isolated as hydrochlorides and their structure proved by IR and for one homologue also by 1H and 13C NMR spectroscopy. A parabolic relationship was found between log activity and molecular lipophilicity (as measured by RM) and the number of carbons in the alkoxy group, thus confirming the results obtained in previous works.

Synthesis and local anesthetic activity of some derivatives of N,N-dimethyl-2-(2-alkoxyphenylcarbamoyloxy)-1,1-dimethylethyl-ammonium chlorides.

A series of 8 new derivatives of 2-alkoxyphenylcarbamoic acid were synthesized and assayed for local anesthetic activity. The above compounds were isolated as hydrochlorides and their structure was proved by 1H NMR, 13C NMR and IR spectroscopy. The index of anesthetic activity of the compounds in infiltration and surface anesthesia increases with the length of the alkyl chain and, except for the C1-C3 congeners, all higher homologues proved to be significantly more active than the standard reference compounds, procaine and cocaine, respectively. Toxicity of the drugs decreases with increasing the chain length and is within acceptable limits.

Synthesis and local anesthetic activity of some derivatives of N,N-diethyl-2-(2-alkoxyphenylcarbamoyloxy)bornan-3-ylmethyl-ammonium chlorides.

A series of 8 new esters of 2-alkoxyphenyl-carbamoic acid were synthesized and assayed for local anesthetic activity. All compounds were isolated as hydrochlorides and their structure was proved by 1H-NMR 13C-NMR and IR spectroscopy. The index of anesthetic activity in infiltration and surface anesthesia proved that all prepared compounds are significantly more active than the standard reference compounds, procaine and cocaine, respectively; it is tightly correlated with the length of the alkoxy group. It was found that there is a parabolic relationship between log activity and molecular lipophilicity (as measured by RM). Toxicity of all compounds is within acceptable limits.

Synthesis and local anesthetic activity of two homological series of diastereomeric phenylcarbamates.

By using stereospecific reactions we prepared two homological series of diastereomeric + cis- and + trans-N,N-dimethyl-2-(2- alkoxyphenylcarbamoyloxy)cyclohexylmethyl-ammonium chlorides with number of carbons in the alkoxy group varying from one to eight. Structure of the prepared compounds was proved by NMR and IR spectroscopy. The principal physico-chemical characteristics, including partition coefficients, were obtained and relative local anesthetic activity was measured using a surface in vivo model. It was found that (1) for both cis- and trans-isomers there is a parabolic relationship between log activity and molecular lipophilicity (as measured by TLC RM and log P values), (2) all drugs prepared for this study use hydrophobic pathway to block inactivated channels, and (3) there is no strict requirement for precise disposition of the functional groups responsible for receptor binding, probably due to conformational flexibility of the sodium channel protein.

Stereoisomeric effect on antimicrobial activity of a series of quaternary ammonium salts.

Two homologous series of diastereoisomeric racemic +/- cis and +/- trans-N,N-dimethyl-N-alkyl-2-benzoyloxycyclohexylmethylammonium bromides with the number of carbon atoms in the alkyl chain from six to twenty (m = 6,8 ... 20) were synthesised. Their structures have been elucidated by IR, UV and in some cases also with 1H and 13C NMR spectrometry. The title compounds were assayed for their antimicrobial activity on microorganisms S. aureus, E. coli and C. albicans. The highest antimicrobial activity was observed against S. aureus (log 1/MIC = 5.5 mol-1 dm3) and the lowest against E. coli (log 1/MIC = 4.5 mol-1 dm3). The +/- cis and +/- trans stereoisomers of all eight couples of diastereoisomeric compounds show differences in their physico-chemical characteristics (including partition coefficient and lipophilicity) which is also reflected in the different antimicrobial activity of these diastereoisomers.

Antimicrobial activity of some salts of dialkylthiophosphoric acids.

A total of 18 derivatives of O,O-dialkylthio- and O,O-dialkylthiophosphoric acids were tested for antimicrobial activity using strains of Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Candida albicans. The activity was found to depend on the length of the alkyl substituent and/or the cation size. All derivatives were ineffective with E. coli and C. albicans.

Can diastereoisomerism of alkoxyphenylcarbamates influence their local anesthetic activity?

The surface local anesthetic activity (LAA) in the homologous series of racemic (+/-)-cis- and (+/-)-trans-N,N-dimethyl-2- (2-alkoxyphenylcarbamoyloxy)cyclopentylmethylamonium chlorides was evaluated. The potency was expressed in rabbits as efficiency indices (EI) in comparison to the standard drug cocaine. All tested racemic mixtures of the phenylcarbamates were local anesthetically active and their potency increased with the size of alkoxysubstitution from the propyloxy- to the hexyloxyderivative and then decreased abruptly (cut-off effect). When different mixtures of both diastereoisomers were applied the synergistic effect--i.e. increase of the LAA of one diastereomer when adding the other--was observed. It seems that an optimal racemic ratio of the compounds could increase their local anesthetic efficiency.

Synthesis of esters of aliphatic and aromatic carbamic acids. A comparative study of properties and local anesthetic activity of these compounds.

Four basic esters of cyclohexancarbamic acid and their salts with hydrochloride were synthesized and evaluated for local anesthetic activity. It was found that also aliphatic carbamates studied exhibit local anesthetic activity comparable with the activity of analogous esters of aromatic (2-methoxyphenyl) carbamic acid. Our comparative investigation shows that the presence of aromatic group in the ester of carbamic acid influences local anesthetic activity, however the occurrence of aromatic moiety is not necessary condition for their activity.

Model compounds in elucidating the structural basis of HIV retrovirus activity. Synthesis of trisodium O-monoalkyl- and O-monoaryldiphosphates.

Trisodium salts of O-methyl, O-butyl, O-phenyl, and O-(4-nitrophenyl)diphosphonic acids were prepared by reaction of sodium dimethylamido-O-(2-cyanoethyl)phosphate with O-alkyl-, and O-arylphosphonic acid. In an effort to obtain anhydrous salts of the acids, besides the conventional method using aqueous sodium hydroxide, another procedure involving reaction, of sodium methoxide in methanol was also used. The structure of the final compounds was confirmed by IR, 1H NMR and 31P NMR spectra. The prepared salts of monosubstituted diphosphonic acids are used as model compounds in studying antiviral and cytostatic activity of phosphorous derivatives of purine and pyrimidine bases.

Metal ion-binding properties of the diphosphate ester analogue, methylphosphonylphosphate, in aqueous solution.

The stability constants of the 1:1 complexes formed between methylphosphonylphosphate (MePP(3-)), CH(3)P(O)(-) (2)-O-PO3(2-), and Mg(2+), Ca(2+), Sr(2+), Ba(2+), Mn(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), or Cd(2+) (M(2+)) were determined by potentiometric pH titration in aqueous solution (25 degrees C; l = 0.1 M, NaNO(3)). Monoprotonated M(H;MePP) complexes play only a minor role. Based on previously established correlations for M(2+)-diphosphate monoester complex-stabilities and diphosphate monoester beta-group. basicities, it is shown that the M(Mepp)(-) complexes for Mg(2+) and the ions of the second half of the 3d series, including Zn(2+) and Cd(2+), are on average by about 0.15 log unit more stable than is expected based on the basicity of the terminal phosphate group in MePP(3-). In contrast, Ba(Mepp)(-) and Sr(Mepp)(-) are slightly less stable, whereas the stability for Ca(Mepp)(-) is as expected, based on the mentioned correlation. The indicated increased stabilities are explained by an increased basicity of the phosphonyl group compared to that of a phosphoryl one. For the complexes of the alkaline earth ions, especially for Ba(2+), it is suggested that outersphere complexation occurs to some extent. However, overall the M(Mepp)(-) complexes behave rather as expected for a diphosphate monoester ligand.